Inner ear lesions can result in permanent balance and hearing deficiencies and have significant negative impact on quality of life. Therefore it is essential to expand the fundamental knowledge of the molecular basis for inner ear deficiencies and develop clinical interventions for their prevention and therapy. This application is to test the influence of two growth factors, glial cell-derived neurotrophic factor (GDNF) and insulin-like growth factor-I (IGF-I) on protection rescue and regeneration in the inner ear. Experiments in the first specific aim of this proposal will test the hypothesis that the IGF-I family of growth factors is necessary and sufficient to enhance repair and regeneration in the sensory epithelia of the inner ear. IGF-I, IGF receptor and IGF-I binding proteins will be localized using in situ hybridization and immunocytochemistry in normal and traumatized inner ears. We will also test the hypothesis that addition of exogenous IGF-I into the perilymph will enhance hair cell regeneration in the mammalian vestibular epithelium, and provide protection in the auditory and balance systems. The second specific aim is to test the hypothesis that viral-mediated transgene expression of GDNF in the cochlear fluids can protect and rescue auditory hair cells and function from temporary and permanent threshold shifts. The third specific aim will test the hypothesis that that infusion of exogenous GDNF into the perilymph leads to GDNF binding to hair cells in the sensory epithelium of the inner ear. We expect that our work will continue to advance auditory and vestibular research towards clinical treatment of environmentally based impairments in the auditory and vestibular systems. The hypothesis driven aims of this proposal are based on recent exciting preliminary data and on innovative in vivo experimental approaches combined with traditional assays. We anticipate that the work will contribute to the understanding of the inner ear response to trauma at the molecular level, and lead to the development of means for protection, rescue, repair and regeneration in the organ of Corti and the vestibular sensory epithelia.